AU642765B2 - Use of N-(1-hexahydroazepinylalkyl)acetamides for the treatment of cholinergic transmission disorders - Google Patents

Abstract

Use of a derivative of formula (I): <IMAGE> in which R, R1, R2 and n are as defined in the description, to obtain medications intended for the treatment of disorders of cholinergic transmission.

Description

P/00/011 28/5/11 Regulation 3.2(2)

AUSTRALIA

Patents Act 1990 6476

ORIGINAL

COMPLETE SPECIFICATION STANDARD PATENT Application Number: Lodged: I. S 4*t~

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C I 511 I. 54 4? 4 4 1 S II

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Invention Title: USE OF N- (1-HEXAHYDROAZEPINYLALKYL )ACETAMIDES Pi !Pig PREPRZ'irWQ ION OF MEnDICAMENS FOR THE TREATMENT OF CROLINERGIC TRANSMISSION DISORDERS Si t The following statement is a full description of this invention, including the best method of performing it known to us t t d~ I_ I ~lllCI 311~ 1 The present invention relates to the use of N-(1hexahydroazepinylalkyl)acetamides in the preparation of medicaments for the treatment of cholinergic transmission disorders.

N-(l-hexahydroazepinylalkyl)acetamides having spasmolytic or vasodilator properties are known from the prior art, especially German Patent DE 2313338.

The Applicant has now discovered that such N-(1hexahydroazepinylalkyl)acetamides possess the surprising property of influencing cholinergic transmission by powerful stimulation of the release of acetylcholine.

The consequence of this activity is an increase in the concentration of acetylcholine in the cholinergic synapse and the *'neuromuscular junction, permitting application in pathologies J3.1, resulting from a central or peripheral cholinergic deficiency, such as Alzheimer's disease, certain intellectual deficiencies as a result of senescence, or myasthenia.

Indeed, a change in nerve impulse transmission in the cholinergic synapses of the central nervous system constitutes 4 t one of the physiological causes of the symptomatology associated Swith Alzheimer's disease (Johns C.A. et al. "The cholinergic treatment strategy in aging and senile dementia".

Psychopharmacol. Bull 1983, 19, 185-187; Collerton D "Cholinergic function and intellectual decline in Alzheimer's disease". Neuroscience 1986, 19, 1-28) and intellectual and cognitive disorders associated with senescence (Davidson M et al.

"Cholinergic mechanisms in the treatment of geriatric disorders" Psychopharmacol Bull, 1986, 22, 101-105).

2- Some of the treatments currently proposed for Alzheimer's disease are moreover based on stimulation of the cholinergic system, either directly as in the administration of parasympathomimetic (arecoline) agents, or indirectly by precursors of acetylcholine (choline, lecithin) which increase the production of acetylcholine in the synaptic region, or by acetylcholinesterase (physostigmine) inhibitors which reduce the enzymatic degradation of the neurotransmitter.

These therapeutic agents, however, have disadvantages associated with the short half-life of the active ingredient and with a feedback that reduces the production of acetylcholine in the neurone.

Myasthenia is characterised by a post-synaptic block of the neuromuscular junction, the contact zone between the motorneurons and the effector muscle (Engel A.G. et al. "Histometric analysis of the ultrastructure of the neuromuscular junction in myasthenia gravis and the myasthenic syndrome". Ann. N.Y. Acad. Sci., 1976, 183, 46-63). The neurotransmitter responsible for the transmission of the nerve impulse at the neuromuscular junction is acetylcholine. While myasthenia is probably of auto-immune origin, it is expressed physiologically in a block of cholinergic transmission and the only medicaments that have exhibited any activity in treating this disease are acetylcholinesterase inhibitors, but their use is limited by the frequency of the side effects they cause.

Substances like the compounds according to the invention that stimulate the release of physiological acetylcholine therefore have a natural application particularly in the *""WWp^Ef

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3 treatment of Alzheimer's disease and related disorders, myasthenia, and any other central or peripheral complaints resulting from a deficiency in cholinergic transmission, and a stimulation of natural release would not be expected to cause any side effects.

More specifically, the invention relates to a method of treatment of an animal afflicted with a cholinergic transmission disorder comprising the step of administering to said mammal an amount of a compound of the general formula I CH -CO -NH -CH n -CH- N R

R

in which: R represents a hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms, n represents 0, 1,2, 3 or 4,

R

1 and R 2 which may be the same or different, represent: a straight-chain or branched alkyl or alkenyl group containing from 1 to 6 carbon atoms, a cycloalkyl group containing from 3 to 7 carbon atoms or a 0. cycloalkenyl group containing from 5 to 7 carbon atoms, 20 an aryl, aralkyl, heteroaryl or heteroaralkyl radical optionally substituted by one or more groups selected from halogen, alkoxy, nitro, trifluoromethyl and hydroxyalkyl, of an isomer thereof, or an addition salt thereof with a pharmaceutically acceptable acid, which is effective for alleviation of the disorder.

Aryl denotes phenyl or naphthyl radicals and heteroaryl denotes furyl, thienyl, pyrrolyl, imidazolyl, benzofuryl, benzothienyl, benzimidazolyl or indolyl radicals.

,^4 4 As pharmaceutically acceptable acids that can be used to convert compounds of the invention into salts, there may be mentioned by way of non-limiting examples hydrochloric, hydrobromic, sulphuric, nitric, oxalic, fumaiic, tartaric, Smethanesulphonic, ethanesulphonic, camphoric, camphorsulphonic, citric, mallic and maleic acid etc.

The compound of formula I, an isomer thereof or a pharmaceutically acceptable salt thereof, are advantageously presented in various forms, such as, for example, tablets, drag6es, gelatin capsules, glossettes or other galenic preparations suitable for sublingual administration, suppositories, solutions for endobuccal pulverisation, galenic preparations suitable for percutaneous administration, and injectable or drinkable solutions.

The dosology can very widely depending on the age of the patient, his weight, the route and the frequency of administration, the seriousness of the complaint from which the i A e i

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Spatient is suffering and associated treatments, and ranges from 0.05 to 150 mg per dose or administration.

The invention is illustrated, in a non-limiting manner, by the activity on cholinergic transmission of the following compounds: compound A the hydrochloride of N-[3-(l-hexahydroazepinyl)-propyl]-diphenylacetamide compound B the hydrochloride of N-[2-(l-hexahydroazepinyl)-ethyl]-diphenylacetamide compound C the hydrochloride of cyclohexyl hexahydroazepinyl)-propyl]-thien-3-ylacetamide, compound D the hydrochloride of cyclohexyl hexahydroazepinyl)-propyl]-benzo[b]thien-2ylacetamide.

SThe tests reported are carried out on the electric organ of Kj the torpedo (Torpedo marmorata), which is known to be embryologically homologous with the cholinergic neuromuscular junctions of higher vertebrates.

EXAMPLE 1 STIMULATION OF THE RELEASE OF ACETYLCHOLINE IN VITRO The cholinergic nerve endings of the electric organ of a torpedo are isolated according to the method described by M.

ISRAEL (Biochem. J. 1976, 160, 113-115). The synaptosomes are purified on a discontinuous density gradient using isoosmotic sucrose/NaCl mixtures approximating to torpedo serum, composed of 250 mM NaCI, 3 mM KC1, 1.8 mM MgC1 2 3.4 irM CaC12, 5 mM NaHCO 3 mM glucose, 300 mM urea and 100 mM sucrose. The pH is

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6 adjusted to a value of 7.1 with 1.2 mM sodium phosphate buffer, after equilibration with 02.

The endings prepared in this manner are capable of synthesising radioactive acetylcholine from labelled precursors (choline and acetate); they are rich in acetylcholine which they are capable of releasing when stimulated.

The release of acetylcholine is triggered, in the presence of 3.5 mM calcium, by the addition of a calcium ionophore, A23187 at a concentration of 3.5 pM, which penetrates the synaptosomal membrane and permits, by electroneutral exchange between the extracellular calcium and the intracellular cations, an increase in the cytoplasmic calcium concentration and the release of the neurotransmitter.

t In practice, 50 pi volumes of the synaptosomal preparation, corresponding to 30 mg of tissue, are diluted in 450 pi of an S alkaline solution approximating to torpedo serum (see above).

The administration of the test compounds in this medium takes 0 place for 3 to 5 minutes before the release of acetylcholine is 0 .1 triggered.

The amount of acetylcholine is determined by the chemiluminescence method described by ISRAEL and LESBATS (J.

'44 Neurochem, 1981, 37, 1475 and Neurochem Int, 1981, 3, 81). The emission of light, which occurs for several minutes, is calibrated immediately after by comparison with an internal standard of acetylcholine. At the end of the release experiment, the addition of Triton X-100 (0.05 causes rupture of the i, synaptosomal membranes, thus allowing the acetylcholine still occluded in the synaptosomes of the sample to be determined.

The compounds used in accordance with the invention exhibit the property of stimulating the release of acetylcholine when that release is induced by ar -icrease in intracellular calcium .il* -IX

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I :1by the addition of the calcium ionophore A 23187 in the presence of calcium, as shown in the following Table: PERCENTAGE RELEASE OF BY THE COMPOUNDS ACETYLCHOLINE INDUCED OF THE INVENTION Concentration Comp s 0 4,9 19,6 49 98 Compounds A 100 102 130 104 123 B 100 ND* 91 116 118 C 100 111 138 136 125 ND not determined Example 2 Injectable solution containing 0.1 mg/ml of the hydrochloride of cyclohexyl hexahydroazepinyl)-propyl ]-thien-3-ylacetamide hydrochloride of cyclohexyl N-[3-(l-hexahydroazepinyl)propyl]-thien-3-yl-acetamide 0.2 g water for injectable preparation, ad 2 1 (quantities for 1000 injectable ampoules each containing 0.2 mg of active ingredient).

-8 EXAMPLE 3: Gelatin capsules each containing 1 mg of the hydrochloride of c y clo he xyl1 N (1hexahydroazepinyl )-propyl I-benzo fbithi en-2--ylacetamide hydrochloride of cyclohexyl N-f 3- -hexahydroazepinyl) propyll-benzo[b]thien-2-ylacetamide 1g *magnesium stearate 5 g *lactose 20 g *colloidal silica 1 g (quantities for 1000 size 2 gelatin capsules each containing 1 mg of active ingredient)

Claims (4)

1. A method of treating a mammal afflicted with a cholinergic transmission disorder comprising the step of administering to said mammal an amount of a compound of formula I: r R1\ 'H -CO -NH -CH -(CH 2 -CH -N R R in which: R represents a hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms, n represents 0,1, 2, 3 or 4, R 1 and R 2 which may be the same or different, represent: 0 a straight-chain or branched aikyl or alkenyl group containing from 1 to 6 carbon atoms, 0 a cycloalkyl group containing from 3 to 7 carbon atoms or a cycloalkenyl group containing from 5 to 7 carbon atoms, an aryl, aralkyl, heteroaryl or heteroaralkyl radical optionally substituted by one or more groups selected from halogen, alkoxy, nitro, trifluoromethyl and hydroxyalkyl, aryl designating phenyl or naphthyl radicals, and heteroaryl designating furyl, thienyl, pyrrolyl, imidazolyl, benzofuryl, benzothienyl, benzimidazolyl or indolyl radicals, an isomer thereof, or an addition salt thereof with a pharmaceutically i acceptable acid which is effective for alleviation of said IB disorder.

2. A method of treatment as claimed in claim 1 comprising the step of o administering -hexahydro-azepinyl)-propyl]-diphenylacetamide, an isomer thereof, or an addition salt thereof with a pharmaceutically acceptable acid. prl i'{1 I~ I_ n_ i 3. A method of treatment as claimed in claim 1 comprising the step of administering N-[2-(1-hexahydro-azepinyl)-ethyl]-diphenylacetamide, an isomer thereof, or an addition salt thereof with a pharmaceutically acceptable acid.

4. A method of treatment as claimed in claim 1 comprising the step of administering cyclohexyl N-[3-(1-hexahydroazepinyl)-propyl]-thien-3- ylacetamide, an isomer thereof, or an addition salt thereof with a pharmaceutically acceptable acid. A method of treatment as claimed in claim 1 comprising the step of administering cyclohexyl N-[3-(1-hexahydroazepinyl-propyl]-benzo[b]thien-2- ylacetamide, an isomer thereof, or an addition salt thereof with a pharmaceutically acceptable acid. i 6. A method of treatment as claimed in any one of claims 1 to wherein said disorder is selected from the group consisting of Alzheimer's i disease, cerebral disorders associated with senescence and myasthenia. j DATED this 21st day of May, 1993 i l UNIVERSITE DE CAEN WATERMARK PATENT TRADEMARK I ATTORNEYS THE ATRIUM 290 BURWOOD ROAD A R HAWTHORN VICTORIA 3122 AUSTRALIA ,3t IIe I II i i r2I 1C. N1< ABSTRACT USE OF N-(1-HEXAHYDROAZEPINYLALKYL) ACETAMIDES IN THE PREPAR!,TION OF -mEnTr FOR THE TREATMENT OF CHOLINERGIC TRANSMISSION DISORDERS u e Vo.oenncaro\ e Car~e-b 14532 Cc-, Ce~c

921-5 COURB-1TE_ CEDEX--- Frccrce The invention relates to the use of a compound of formula (I) R1 CH-CO-NH- CK-(CH2)- CH- N R2R R io in which R, R 1 R 2 and n are as defined in the description, for the treatment of cholinergic transmission disorders. FA V;a~